Contemporary drug therapy approaches are mainly based on the development of new therapeutic molecules as well as on the advancement of combined treatment schedules. However, clinical efficacy of these approaches is inherently limited by their physical-chemistry, pharmacokinetics and cross-reactivity attributes, inadvertently arising from a restricted concentration at the intended site of action and an extensive overall bio-distribution.
In an effort to address this challenge, the emerging command of nanotechnology is facilitating the delivery of drug molecules to non-healthy organs, tissues and/or cells. The most advanced nanotechnology inspired drug delivery platforms are focused on the entrapment of therapeutically active molecules in synthetic lipid-based carrier systems. Encapsulation facilitates the isolation of a drug from the in vivo environment, hereby overcoming a drug's non-ideal properties, including limited solubility, serum stability, circulation half-life and biodistribution.
The ideal synthetic nanocarrier which is composed of non-toxic constituents and is specifically internalized by target cells remains elusive to date. Therefore, these systems don't harness the full potential that nanotechnology can provide. Insights into how molecules are transmitted in nature may provide the blueprint for efficient and biocompatible drug delivery vehicles.
It is known that cells exchange information through the secretion of soluble factors or by direct interaction. Recent studies have come to the conclusions that cells also release membrane-derived vesicles that have an impact on both neighboring and distant cells (Marcus & Leonard, 2013). These extracellular vesicles are secreted by most cells, and are physiological constituents of most biological fluids (Vlassov, Magdaleno, Setterquist, & Conrad, 2012). Extracellular vesicles entail the subtypes apoptotic bodies, microvesicles, and exosomes (E L Andaloussi, Mäger, Breakefield, & Wood, 2013)
Although the research on how extracellular vesicles can act as mediators of intercellular communication is still in its early stages, exploring their inherit role in delivering bioactive cargo from “donor” cells to “recipient” cells is contributing valuable insights into the complexity of optimal drug delivery. Various studies have identified several conditions in which extracellular vesicles can function as therapeutic carriers. There is increasing evidence that these carriers possess distinct characteristics rendering them pharmaceutically superior to synthetic drug carriers. Of particular significance for this superiority is a collection of membrane proteins and distinct lipids integrated in the surface composition of extracellular vesicles.
Several obstacles exist that hinder exploiting or mimicking natures' carriers for efficient drug delivery systems. Most notably, transforming extracellular vesicles from message couriers to drug carriers requires the introduction of therapeutic or diagnostic molecules exogenous to the “donor” cell. The respective engineering methodologies proposed to date include the use of bioengineering procedures on “donor” cells (i.e. genetic modification, viral transfection, toxic cationic lipofection, etc.) as well as vigorous or damaging manipulation mechanisms applied to isolated vesicles (i.e. electroporation, conjugation chemistry, etc.). These methods ultimately raise safety as well as scalability concerns and hamper a translation into the clinic. Other important issues that still need to be addressed include control over structural integrity of the carrier, efficient encapsulation of active cargo and the incorporation of additional targeting moieties.
Ideally, intricate bio-mimetic functionalization approaches requiring numerous bioactive membrane components incorporated into a synthetic nanocarrier could be circumvented if intact extracellular vesicle membranes would be exploited. Conversely, in order to overcome the dire consequences of biotechnological protocols, strategies to introduce therapeutic as well as targeting components exogenous to the extracellular vesicles, should preferably be independent of cellular manipulation. Based on these premises, it may be beneficial to replace bioengineering techniques with nanotechnological strategies employed in modern nano-particular drug delivery systems.
In view of the shortcomings mentioned above, it is an object of the invention to provide a novel pharmaceutical carrier with highly defined attributes, lacking the drawbacks of prior art carriers while synergizing the advantages of ex-vivo generated synthetic nanocarriers and in vivo occurring extracellular vesicles.
It is another object of the invention is to provide a pharmaceutical composition comprising said novel pharmaceutical carrier.
It is a further object of the invention to provide uses and methods based on said novel pharmaceutical carrier or a pharmaceutical comprising it for the treatment, monitoring, prevention, staging and/or diagnosis of a disease or condition
It is a further object of the invention to provide a process for manufacturing said novel pharmaceutical carrier in a controllable way involving stimuli-responsive modules.
It is a further object of the invention to provide a method for delivering one or more bioactive agents into a cell, more particularly a cell selected from a leukocyte, a glial cell and a stem cell.
It is a further object of the invention to provide a method to produce the above pharmaceutical carrier in a controllable way involving stimuli-responsive modules.
Further purposes and advantages of this invention will appear as the description proceeds.